About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

June 22, 2009

Funky Carbocycles

Posted by Derek

Earlier this month I posted about rolofylline, which I noted has a rather unusual noradamantane attached to it. Now check out this ORL-1 compound from Banyu, complete with the not-so-widely-heard-of bicycloheptane-spirocyclopropane group.

This was not arrived at lightly, as you'd imagine. There's a table in the Supporting information for the paper, but I'll quote from the body of the main manuscript:

Sadly it seems that many of us in med chem tend to spend way too much time optimizing grease.

I have never worked in the CNS area, but it appears to me that many of the successful modulators are of the small MW variety with some grease, a tertiary basic group, and some other spinach.

So, it appears that many times the space available for novelty becomes some new variant of the greasy portion, although I have seem some pretty funky piperidine/piperazine surrogates. I would expect the Banyu guys may have just killed two birds with one stone in this case, activity and patentability.

Derek, since you have some experience in this area, are my observations correct or skewed?

It seems that another place grease optimization comes up is in some of the steroid mimics that inhibit the various metabolic steroid-processing enzymes (where there are large hydrophobic cavities). I remember Merck's candidate (I believe it was called Compound 544), for inhibition of 11-beta hydroxysteroid dehydrogenase was one of a large class of adamantyl triazoles They arrived at this structure after going through a long series of bulkier carbocycles and various things like cyclooctane, with adamantyl becoming a case of The Only Thing That Works There.

There seems to be something about unusual aliphatic polycyclic hydrocarbons - they are sometimes far more stable to metabolic oxidation than I would have guessed they'd be. I haven't seen any good explanation for the "rules" that govern this behavior - anyone have any good references or ideas?